Biphenydiols

ABSTRACT

The invention relates to the biphenyldiols of the formula (V) 
                 
 
     The corresponding racemic and enantiomerically pure triflate compounds thereof, where R 1  and R 2  are H, R 3  is chlorine, and R 4  is methoxy. 
     In an alternate embodiment, R 1  and R 2  are hydrogen and R 3  and R 4  are C 1 -C 4 -alkoxy, fluorine, or chlorine.

This is a Divisional Application of U.S. Ser. No. 10/219,750, now U.S.Pat. No. 6,566,298, filed Aug. 15, 2002, which in turn is a DivisionalU.S. Ser. No. 09/948,826, now U.S. Pat. No. 6,462,200 filed Sep. 7,2001.

BACKGROUND OF THE INVENTION

The present invention relates to a process for the preparation ofracemic diphosphines, to a process for the preparation ofenantiomerically pure diphosphines, to novel enantiomerically purediphosphines, to novel intermediates for the preparation ofdiphosphines, and to catalysts that contain novel diphosphines.

A process that differs greatly from the process according to theinvention for the preparation of diphosphines is known from EP-A749,973. According to this, if the intention is to prepareenantiomerically pure diphosphines, the racemate resolution is carriedout at the stage of the phosphine oxides, i.e., for individualdiphosphines separate racemate resolutions must be carried out.Compounds different from the compounds according to the invention aredescribed in EP-A 104,375, EP-A 582,692, and EP-A 690,065. Racemateresolutions with N-benzylcinchonidinium chloride have hitherto beendescribed only for dinaphthol compounds (Tetrahedron Lett. 36, 7991(1995)).

SUMMARY OF THE INVENTION

Specifically, the present invention first relates to a process for thepreparation of racemic diphosphines of the formula (I)

in which

-   R is C₆-C₁₄-aryl or C₄-C₁₃-heteroaryl containing 1 to 3 heteroatoms    selected from the group consisting of nitrogen, oxygen, and sulfur,    wherein the aryl and heteroaryl radicals may optionally be    substituted by halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, and/or    trimethylsilyl, and-   R¹ to R⁴, independently of one another, are each hydrogen,    C₁-C₁₀-alkyl, C₁-C₁₀-alkoxy, F, Cl, or Br,-   comprising    -   (a) converting a phenol of the formula (II)    -    in which R¹ to R⁴ have the meanings given for formula (I), into        the corresponding phenoxide using a base,    -   (b) reacting the phenoxide with dihalogenomethane to give a        formaldehyde acetal of the formula (III)    -    in which R¹ to R⁴ have the meanings given for formula (I),    -   (c) intramolecularly oxidatively coupling the formaldehyde        acetal of the formula (III) to give a cycloheptadiene of the        formula (IV),    -    in which R¹ to R⁴ have the meanings given for formula (I),    -   (d) converting the cycloheptadiene of the formula (IV) by        treatment with an acid into a biphenyldiol of the formula (V)    -    in which R¹ to R⁴ have the meanings given for formula (I),    -   (e) preparing the corresponding triflate from the biphenyldiol        of the formula (V), and    -   (f) coupling the triflate with a secondary phosphine of the        formula (VI)        HPR₂  (VI),    -    in which R has the meaning given for formula (I), with the        addition of a base and in the presence of a palladium(0),        palladium(II), nickel(0), and/or Ni(II) compound, thereby giving        a compound of the formula (I).

DETAILED DESCRIPTION OF THE INVENTION

In the formulas (I) to (V), R¹ and R² are preferably hydrogen and R³ andR⁴ are preferably C₁-C₅-alkoxy, fluorine, or chlorine. In the formulas(I) and (VI), R is preferably phenyl, furyl, or 2-N—C₁-C₆-alkylpyrrolylthat may optionally be substituted by 1 to 3 substituents from the groupconsisting of fluorine, chlorine, C₁-C₅-alkyl, C₁-C₆-alkoxy, andtrimethylsilyl. In the formulas (I) to (V), R¹ and R² are particularlypreferably hydrogen, R³ is particularly preferably chlorine, and R⁴ isparticularly preferably methoxy or ethoxy. In the formulas (I) and (VI),R is particularly preferably phenyl, 2-furyl, 2-N-methylpyrrolyl,3,5-dimethylphenyl, 4-fluorophenyl, 4-tolyl, or 3,5-dimethoxyphenyl.

In the conversion of the phenol of the formula (II) into thecorresponding phenoxide, the base that can be used is, for example, analkali metal hydride, hydroxide, or carbonate. Preference is given tosodium hydride and potassium hydride. The base is preferably used in anamount of from 0.9 to 1.5 equivalents per mole of phenol of the formula(II). Here, it is possible to work in the presence of a solvent, e.g.,in the presence of a dipolar-aprotic solvent, such as dimethylformamide,or an ether, such as diethyl ether, tetrahydrofuran, dioxane, or methyltert-butyl ether.

Suitable reaction temperatures, particularly when alkali metal hydridesare used as base, are, for example, those in the range from −20 to +60°C. It is advantageous to carry out this stage under a protective gasatmosphere. The procedure may involve, for example, initiallyintroducing the base together with the solvent and metering in thephenol of the formula (II) dissolved in the same solvent.

The phenoxide obtained does not need to be isolated. Particularly if theprocess has been carried out with stoichiometric amounts of alkali metalhydride as base, the reaction mixture that is present following reactionwith the base can be further used directly.

In the reaction with the phenoxide it is possible to use, based on onemole of phenol of the formula (II) originally used, e.g., 0.4 to 0.7 molof dihalogenomethane. Suitable reaction temperatures are, for example,those from 0 to 80° C., particularly those from 10 to 60° C. Thereaction time for the reaction with the dihalogenomethane can be, forexample, 8 to 40 hours. Suitable as dihalogenomethane is, for example,dichloromethane, dibromomethane, and diiodomethane. Diiodomethane ispreferred.

The reaction mixture that is then present can be worked up, for example,by extracting it after addition of water with a virtually nonpolar ornonpolar organic solvent and removing the solvent from the extract. Theresidue that remains can, if desired, be further purified, for example,by dissolving it in an ether, in methanol, or in acetonitrile atelevated temperature, discarding the insoluble components, and obtainingthe prepared formaldehyde acetal of the formula (III) in purified formby crystallization.

The intramolecular oxidative coupling for the preparation of acycloheptadiene of the formula (IV) can be carried out, for example, byfirst adding an organolithium compound to the formaldehyde acetal of theformula (III) and, when they have finished reacting, adding an oxidizingagent. For example, it is possible to add butyllithium dissolved in, forexample, a hydrocarbon to a solution of the formaldehyde acetal, forexample in ether, at −30 to +40° C. and leave the mixture to fully reactby after-stirring at a temperature in this range. Per mole offormaldehyde acetal, it is possible to use, for example, 2.0 to 2.2 molof organolithium compound. In general, the reaction is complete after 5to 30 hours. The oxidizing agent can then be added, for example aCu(II), Fe(III), Mn(III), or Ce(IV) compound. The oxidative coupling canalso be carried out enzymatically, e.g., with a peroxidase. Theoxidizing agent is added at, for example, −70 to −30° C., and themixture is subsequently warmed to a temperature of, for example, below50° C. Based on 1 mol of formaldehyde acetal of the formula (III) used,it is possible to use, for example, 2.0 to 2.5 equivalents of anoxidizing agent. It is advantageous to continue to after-stir thereaction mixture in conclusion, e.g., for 1 to 5 hours.

It is also possible to carry out the oxidative coupling directly fromthe formaldehyde acetal of the formula (III) in accordance with themethods described here without converting said formaldehyde acetal intothe Li salt beforehand.

It is advantageous at least to carry out the reaction with theorganolithium compound under a protective gas atmosphere.

The treatment with an acid to convert a cycloheptadiene of the formula(IV) into a biphenyldiol of the formula (V) can be carried out, forexample, with a strong mineral acid such as hydrochloric acid orsulfuric acid. For example, 5 to 15 equivalents of acid can be used permole of cycloheptadiene of the formula (IV). The procedure isexpediently carried out in the presence of a solvent, for example in thepresence of an alcohol. The treatment with the acid can be carried out,for example, in a period of from 5 to 50 hours at temperatures of from50 to 100° C. The reaction mixture can be worked up, for example,analogously to the procedure described above for the preparation offormaldehyde acetals of the formula (III).

The preparation of the triflate compound (i.e., atrifluoromethane-sulfonic ester) from the biphenyldiol of the formula(V) can be carried out, for example, by suspending the biphenyldiol ofthe formula (V) in a solvent (e.g., an aromatic hydrocarbon), adding atertiary amine (e.g. pyridine), and then metering in, for example,trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride,optionally dissolved in a solvent (e.g., in an aromatic hydrocarbon),and after-stirring. The metered addition and after-stirring can becarried out, for example, at 0 to 60° C. A suspension forms during thisoperation. Per mole of biphenyldiol of the formula (V), it is possibleto use, for example, 2 to 3 mol of a tertiary amine and 2 to 2.2 mol oftrifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride.

For work-up, the reaction mixture can, for example, be washed with waterand aqueous sodium chloride solution, the organic phase that is leftbehind can be dried, and the solvent can be removed, where necessary bystripping it off under reduced pressure. The product obtainable in thisway is pure enough for the reaction with secondary phosphines. Ifdesired, it can be further purified, e.g., by (flash) columnchromatography.

For the reaction of the triflate compound with a secondary phosphine ofthe formula (VI), the base that may be used is, for example, a tertiaryamine (for example, a trialkylamine), that contains three identical ordifferent C₁-C₆-alkyl groups. Arylalkylamines, DABCO, “proton sponges”(e.g. 1,8-bis(dimethylamino)naphthalene) and hydrogen carbonates, suchas sodium hydrogen carbonate, are also possible. Preference is given tousing triethylamine or ethyl-diisopropyl-amine. The amount of base used,based on one mole of the triflate compound, can, for example, be 2 to 3mol.

Suitable palladium(0) or nickel(0) compounds are, for example complexesof the formulas (VIIa) and (VIIb),Pd(PR′₃)₄  (VIIa)Ni(PR′₃)₄  (VIIb)in which

-   R′ is in each case C₁-C₁₀-alkyl or C₆-C₁₄-aryl, where aryl may    optionally be substituted by halogen and/or C₁-C₆-alkyl, and where    R′ is preferably phenyl.

Also suitable as palladium(0) compound is Pd₂(dba)₃, where dba isdibenzylideneacetone. The Pd₂(dba)₃ can optionally also contain acoordinated solvent molecule, e.g., CHCl₃.

It is also possible to use a palladium(0) compound of the formula (VIIc)Pd(L₂)  (VIIc),in which

-   L is R′₂P—(CH₂)_(n)—PR′₂, diphenylphosphinoferrocenyl, or    2,2′-bis-(diphenylphosphinomethyl)-1,1′-binaphthyl, where R′ has the    meaning given above and n is 1, 2, 3, or 4.

Preferred compounds of the formula (VIIc) are those in which L is

-   R′₂P—(CH₂)_(n)—PR′₂, where R′ is phenyl and n is 2, 3, or 4.

Suitable as palladium(II) compound is, for example, Pd(CH₃COO)₂, andsuitable as nickel(II) compound, for example, NiCl₂ that optionally alsocontains 1 to 2 coordinated PR′₃-molecules (where R′ has the samemeaning as in the formulas (VIIa) and (VIIb)).

Preference is given to using palladium(0) compounds of the formulas(VIIa) and (VIIc) and Pd₂(dba)₃. These compounds can, if desired, alsobe prepared in situ, for example, by initially introducing palladiumdiacetate into a solvent and adding the ligands in thestoichiometrically required amount or in an excess of up to, forexample, 150% of the stoichiometrically required amount.

The amount of palladium and/or nickel compounds used, based on 1 mol oftriflate compound, can be, for example, 0.001 to 0.1 mol.

The reaction of the triflate compound with a secondary phosphine of theformula (VI) can be carried out, for example, by initially producing thepalladium(0), palladium(II), nickel(0), and/or nickel(II) compound in adipolar-aprotic solvent or preparing said compound in situ in adipolar-aprotic solvent, and then bringing it together with thesecondary phosphine of the formula (VI), the base, the triflatecompound, and optionally further solvent. It is also possible to preparea mixture as described above that contains the palladium and/or nickelcompound, to add this mixture to an initial charge of triflate compound,and then to add base, secondary phosphine of the formula (VI), andoptionally further solvent. The preparation of the mixture containingpalladium and/or nickel compounds can be carried out, for example, at−10 to +40° C., and the reaction with the triflate compound can becarried out at, for example, 20 to 160° C. The reaction of the triflatecompound can require, for example, reaction times in the range from 5 to200 hours.

Isolation and purification of the diphosphine compound of the formula(I) prepared in this way can be carried out, for example, by firststripping off the solvent at elevated temperature under reducedpressure, taking up the residue with toluene, passing this mixture overa silica column, taking the fraction containing the prepareddiphosphine, stripping off the toluene therefrom, dissolving the residuein dimethylformamide, and crystallizing the prepared diphosphine bylayering with methanol or dialkyl ether.

The present invention further relates to a process for the preparationof enantiomerically pure diphosphines of the formula (VIII)

in which the symbols used have the meanings given for formula (I), andof a formula that is analogous to formula (VIII) but represents theother enantiomer.

This preparation is carried out according to the invention like theabove-described preparation of the racemic diphosphines of the formula(I) and is additionally characterized in that the biphenyldiol of theformula (V) is subjected to racemate resolution. The racemate resolutioncan be carried out, for example, by crystallization using an auxiliaryreagent or by chiral chromatography, e.g., according to the SMB method.Suitable auxiliary reagents for the racemate resolution bycrystallization are, for example, tartaric acid derivatives andcinchonine derivatives.

For this purpose, preference is given to using(−)-O,O′-dibenzoyl-L-tartaric acid or enantiomerically pureN-benzylcinchonidinium chloride. Per mole of biphenyldiol, it ispossible to use, for example, 0.5 to 1 mol of auxiliary reagent.

The racemate resolution can, for example be carried out by refluxing theracemic biphenyldiol of the formula (V) together with the auxiliaryreagent in a suitable solvent, e.g., a C₁-C₄-alkyl alcohol oracetonitrile for a few hours, after-stirring, filtering off theprecipitate that is present, and taking it up in a water-immisciblesolvent (e.g., a chloro-alkane, an aromatic hydrocarbon, or ethylacetate), washing with an acid, e.g., a dilute mineral acid, separatingoff the organic phase, extracting the aqueous phase with awater-immiscible solvent, and stripping off the solvent from thecombined organic phases.

The remaining preparation of enantiomerically pure diphosphines of theformula (VIII) is then carried out as described above for thepreparation of racemic diphosphines.

The present invention further relates to enantiomerically purediphosphines of the formula (IX)

in which the radicals R″ are in each case identical and are 2-furyl,2-N-methylpyrrolyl, 4-fluorophenyl, 3,5-dimethoxyphenyl, or3,5-dimethylphenyl, and of a formula that is analogous to formula (IX)but represents the other enantiomer.

The present invention further relates to cycloheptadiene compounds ofthe formula (IV), to racemic and enantiomerically pure biphenyldiols ofthe formula (V), and to the corresponding racemic and enantiomericallypure triflate compounds accessible from the biphenyldiols of the formula(V), wherein in the triflate compounds in each case R¹ and R² are H, R³is chlorine, and R⁴ is methoxy.

The racemic diphosphines of the formula (I) prepared according to theinvention and the novel enantiomerically pure (+)- and (−)-diphosphinesof the formula (VIII) are suitable as ligands for the preparation ofcatalysts, preferably of catalysts for hydrogenation. Theenantiomerically pure (+)- and (−)-diphosphines of the formula (VIII)are particularly suitable as ligands for the preparation ofhydrogenation catalysts for enantioselective hydrogenations.

Said ligands may, in order to be successful as hydrogenation catalysts,be combined with metals, including in the form of metal ions or metalcomplexes of elements of subgroup VIII of the Periodic Table of theElements. In this connection, ruthenium, iridium, and rhodium arepreferred. Here, the ligand-metal combination may be undertakenseparately or in situ within the reaction mixture for the hydrogenation.In this connection, 0.5 to 10 mol (preferably 1 to 5 mol) of saidligands, for example, may be used per mole of metal.

The racemic diphosphines of the formula (I) can, for example, be usedadvantageously as ligands for palladium catalysts used in aminationreactions. Numerous intermediates for pharmaceutical and crop protectionactive ingredients are accessible by palladium-complex-catalyzedaminations. It has hitherto been known to use binaphthylphosphoruscompounds as ligands for such aminations.

Finally, the present invention also relates to catalysts that contain ametal, a metal ion or a metal complex of an element of subgroup VIII ofthe Periodic Table of the Elements and at least one diphosphine of theformula (IX). These catalysts preferably contain, independently of oneanother, ruthenium, iridium, or rhodium and 0.5 to 10 mol of adiphosphine of the formula (IX) per mole of metal, metal ion, or metalcomplex.

In the process according to the invention for the preparation of racemicdiphosphines of the formula (I), it is advantageous that a broad paletteof different ligands is accessible directly from one precursor (i.e., acompound of the formula (VI)). For example, it is readily possible toprepare different ligands, tailored to a specific catalyst problem, thathave different electronic and steric ratios.

In the process according to the invention for the preparation ofenantiomerically pure diphosphines of the formula (VIII), it isadvantageous that the phosphine radicals are introduced only after theracemate resolution. As a result, it is possible to carry out thecomplex racemate resolution for diverse diphosphines in a common initialstage and only then prepare a broad spectrum of individual diphosphines.Separate racemate resolutions for individual diphosphines can thus beavoided.

The enantiomerically pure diphosphines of the formula (IX) according tothe invention have the advantage that catalysts that can be preparedtherefrom are superior to other catalysts in different reactions withregard to the enantiomer excess that is achievable following their use.Ruthenium catalysts with enantiomerically pure ligands according to theinvention are, for example, advantageous for the enantioselectivehydrogenation of heteroaromatic ketones and itaconic acid derivatives.

The cycloheptadiene compounds, biphenyldiols, and triflate compoundsaccording to the invention are novel intermediates for the preparationof novel diphosphines, from which catalysts with superior properties canbe prepared.

The following examples further illustrate details for the process ofthis invention. The invention, which is set forth in the foregoingdisclosure, is not to be limited either in spirit or scope by theseexamples. Those skilled in the art will readily understand that knownvariations of the conditions of the following procedures can be used.Unless otherwise noted, all temperatures are degrees Celsius and allpercentages are percentages by weight.

EXAMPLES Example 1 Preparation of Formaldehydebis(4-chloro-3-methoxyphenyl) Acetal (IUPAC:bis(4-chloro-3-methoxyphen-1-oxy)methane)

A solution of 100 g of 4-chloro-3-methoxyphenol in 250 ml ofdimethylformamide was slowly added dropwise to a suspension of 16.0 g ofsodium hydride (95% strength) in 300 ml of dimethylformamide under argonat 0° C. When the addition was complete, the mixture was after-stirredfor a further 1 hour at 40° C., giving a clear, yellow solution. At roomtemperature, a solution of 88.1 g of diiodomethane in 100 ml ofdimethylformamide was then slowly added dropwise. The solution wasstirred for 15 hours at room temperature, during which an orange-redsuspension gradually formed. The mixture was then stirred for a further3 hours at 50° C. 400 ml of water were added and the mixture wasextracted with 3×150 ml of methylene chloride. The combined organicphases were washed with 3×100 ml of saturated aqueous sodium chloridesolution, the organic phases were dried over sodium sulfate, and thesolvent was removed at 50° C. under reduced pressure, giving anorange-brown solid residue. This residue was dissolved in 250 ml ofmethyl tert-butyl ether at the boil, decanted off from the oily residuepresent and concentrated by evaporation until precipitation occurred.The mixture was left to crystallize first at room temperature and then,to complete the precipitation, at +4° C. The precipitate was filteredoff and carefully washed with 1:1 methyl tert-butyl ether/petroleumether. The mother liquor was concentrated by evaporation and left tocrystallize again.

Yield: 85.2 g (82% of theory) Melting point: 110° C.

By removing the DMF prior to work-up with dichloromethane/water, it ispossible to increase the chemical yield from 82 to 90%. The intenselycolored phenol oxidation products that are present can be separated offby flash column chromatography over silica gel with dichloromethane aseluent.

¹H-NMR (CDCl₃): δ=3.87 (s, 6H, CH₃); 5.68 (s, 2H, CH₂); 6.65-6.70 (m,4H, H_(arom.)); 7.27 (d, ³J_(H-H)=8.1 Hz, 2H, H_(arom.)) ¹³C-NMR(CDCl₃): δ=56.2 (CH₃); 91.4 (CH₂); 102.0 (C_(arom.)); 108.2 (C_(arom.));116.2 (C_(arom., ipso)); 130.4 (C_(arom.)); 155.7 (C_(arom., ipso));156.5 (C_(arom., ipso))

Example 2 Preparation of2,10-dichloro-1,11-dimethoxy-5,7-dioxadibenzo[a,c]cycloheptadiene

239 ml of a 1.6 molar solution of butyllithium in hexane was slowlyadded dropwise to a solution of 60 g of formaldehyde[bis(4-chloro-3-methoxyphenyl) acetal] (IUPAC:bis(4-chloro-3-methoxyphen-1-oxy)-methane) in 100 ml of tetrahydrofuranat 0° C. under argon. When the addition was complete, the mixture wasstirred for 15 hours at room temperature, giving a yellow suspension.The reaction mixture was then cooled to −50° C., and 51.3 g of anhydrouscopper(II) chloride were added. The solution was then left to warm toroom temperature over the course of 5 hours, and then 300 ml of waterand 200 ml of methylene chloride were added. The mixture was neutralizedwith 50 ml of 2N aqueous hydrochloric acid, and then the resultingwhite-grey precipitate was redissolved by adding 300 ml of 25% strengthaqueous ammonia solution. The methylene chloride phase was separated offand the deep dark-blue aqueous phase was further extracted with 5×100 mlof methylene chloride. The organic phase was then washed a few moretimes using a total of 400 ml of saturated aqueous ammonium chloridesolution until it was only just still pale blue in color. The organicphase was concentrated somewhat by evaporation, dried over sodiumsulfate, and all of the solvent was removed, giving a brown solid, whichwas treated with 100 ml of boiling methyl tert-butyl ether. The solutionformed was decanted off from the oily residue and the solution was leftto crystallize at +4° C. The solid that precipitated out was filteredoff and the solvent was then removed from the filtrate under reducedpressure, and the residue that formed during this operation wassubjected to column-chromatographic purification with silica gel 60 andwith toluene as eluent. The yellow eluate was freed from the solventunder reduced pressure, and the residue was dissolved again in 40 ml ofboiling methyl tert-butyl ether and left to crystallize at +4° C.

Yield: 45.4 g (77% of theory)

By drying the copper(II) chloride over P₄O₁₀ at 140° C. beforehand andby using an equimolar mixture of n-butyllithium andN,N,N,N-tetramethyl(ethylenediamine) (TMEDA) it is possible to achieve avery selective aromatic coupling to give the desired product (crude NMRshows only one product).

The removal of the THF prior to work-up and an acidic work-up with 4 NHCl has also proven advantageous.

The yield can be increased by these measures to 95% of theory. Meltingpoint: 130° C. ¹H-NMR (CDCl₃): δ=3.60 (s, 6H, OCH₃); 5.46 (s, 2H,OCH₂O); 6.94 (d, ³J=8.7 Hz, 2H, H_(arom.)); 7.43 (d, ³J=8.7 2H,H_(arom.)) ¹³C-NMR (CDCl₃): δ=61.2 (CH₃); 102.3 (CH₂); 117.0(C_(arom.)); 124.1 (C_(arom., ipso)); 124.9 (C_(arom., ipso)); 130.8(C_(arom.)); 152.1 (C_(arom., ipso)); 154.4 (C_(arom., ipso))

Example 3 Preparation of 5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diol

4 ml of concentrated aqueous hydrochloric acid were added to asuspension of 1.76 g of2,10-dichloro-1,11-dimethoxy-5,7-dioxadibenzo-[a,c]cycloheptadiene in 25ml of ethanol. The mixture was then refluxed under argon for 21 hours,the course of the reaction being monitored by means of thin-layerchromatography using methylene chloride as eluent. The resulting clear,yellow solution was admixed with 30 ml of water, extracted with 2×50 mlof methylene chloride, and washed with 2×50 ml of saturated aqueoussodium chloride solution. The organic phase was dried over sodiumsulfate and filtered, and the solvent was removed under reducedpressure. The residue was carefully triturated with cold chloroform,which was decanted off again and discarded.

Yield: 1.54 g (91% of theory)

By adding 1.5 equivalents of ethylene glycol, based on the molar amountof the acetal used, the yield can be increased to 99% of theory.

Melting point: 110° C. ¹H-NMR (CDCl₃): δ=3.66 (s, 6H, OCH₃); 5.29 (s,2H, OH); 6.84 (d, ³J_(H-H)=9.0 Hz, 2H, H_(arom.)); 7.37 (d, ³J_(H-H)=8.72H, H_(arom.)) ¹³C-NMR (CDCl₃): δ=61.1 (CH₃); 114.4 (C_(arom.)); 115.2(C_(arom. ipso)); 119.1 (C_(arom., ipso)); 131.5 (C_(arom.)); 153.6(C_(arom., ipso)); 153.8 (C_(arom., ipso))

Example 4 Preparation of(+)-5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diol

A suspension of 22.9 g of 5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-dioland 16.0 g of N-benzylcinchonidinium chloride in 110 ml of acetonitrilewere refluxed for 4 hours and then stirred for 15 hours at roomtemperature. The resulting precipitate was filtered off, washed with asmall amount of acetonitrile, and dried under reduced pressure. Theresidue was taken up in 250 ml of ethyl acetate and extracted by shakingwith 2×50 ml of aqueous 2N hydrochloric acid. The organic phase wasseparated off, and the aqueous phase was extracted again with 2×50 ml ofethyl acetate. The combined organic phases were washed with 4×100 ml ofsaturated aqueous sodium chloride solution, dried over sodium sulfate,and filtered, and the solvent was removed under reduced pressure.

Yield: 6.77 g (30% of theory) Enantiomer purity: 98.4 e.e.

The enantiomer purity was checked using analytical HPLC. The eluent usedwas n-heptane/isopropanol 80:20

[α]_(D)=+23.6 (c=1.5; CHCl₃)

Subsequent recrystallization from chloroform gave a product with anenantiomer purity of more than 99.9% e.e.

Example 5 Preparation of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)bistrifluoro-methanesulfonic Acid Ester

3.4 g of (+)-5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diol weresuspended in 40 ml of toluene, and 2.5 g of pyridine were added, aclear, pale brown solution being formed within 10 min. A solution of 6.9g of trifluoromethanesulfonic anhydride in 5 ml of toluene was added tothis solution dropwise at room temperature. A flocculant precipitateformed rapidly. The mixture was stirred for 3 hours at 45° C., duringwhich an orange-colored suspension was formed. This suspension waswashed with 2×20 ml of water and then with 2×30 ml of saturated aqueoussodium chloride solution. The organic phase was dried over sodiumsulfate and filtered, and the solvent was removed at 50° C. underreduced pressure, giving an orange-colored oil. This was pure enough tobe further used directly. If desired, the oil could be further purifiedby flash column chromatography on silica gel with toluene as eluent.

Yield of oil: 5.7 g (92% of theory) ¹H-NMR (CDCl₃): δ=3.77 (s, 6H,OCH₃); 5.29 (s, 2H, OH); 7.18 (d, ³J_(H-H)=9.0 Hz, 2H, H_(arom.)); 7.58(d, ³J_(H-H)=9.0 Hz, 2H, H_(arom.)) ¹³C-NMR (CDCl₃): δ=61.5 (CH₃); 117.2(C_(arom.)); 118.3 (q, ¹J(C, F)=320 Hz, CF₃); 121.1 (C_(arom. ipso));127.8 (C_(arom., ipso)); 132.3 (C_(arom.)); 145.9 (C_(arom., ipso));155.9 (C_(arom., ipso)) ¹⁹F-NMR (CDCl₃): δ=74.9 (s, CF₃)

Example 6 Preparation of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(diphenylphosphine)

220 mg of Pd(PPh₃)₄ were added with 75 mg of diphenylphosphinopropane to10 ml of dimethyl sulfoxide under argon, and the mixture was stirred for3 hours at room temperature, during which time an orange-coloredsuspension formed. To this suspension were added 0.99 g ofdiphenylphosphine, 0.85 g of N,N-diisopropylethylamine, 1.00 g of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bistrifluoromethanesulfonicacid ester, and a further 10 ml of dimethyl sulfoxide, and the clear,yellow solution was then stirred at 100° C. for 79 hours. When thereaction was complete, the solvent was removed under reduced pressure at100° C., and 10 ml of methanol were added to the residue and left tocrystallize at −25° C. The resulting fine precipitate was filtered offand washed with methanol.

Yield: 0.70 g (62% of theory).

The NMR data were identical to those given in EP-A 749,973.

Example 7 Preparation of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(bis-2-furylphosphine)

100 mg of Pd₂(dibenzylideneacetone)₃.CHCl₃ were suspended together with80 mg of diphenylphosphinopropane in 10 ml of dimethylformamide underargon, and the mixture was stirred for 2 hours at room temperature,during which time a clear, orange-colored solution formed. This solutionwas transferred using a hollow needle to a Schlenk vessel, in which 3.40g of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bistrifluoromethanesulfonicacid ester had been introduced. A further 10 ml of dimethylformamide,1.56 g of triethylamine and 1.00 g of di-2-furylphosphine were added tothis solution, and the mixture was stirred for 72 hours at 100° C., afurther 1.03 g of bis-2-furylphosphine being added after 22 hours. Whenthe reaction was complete, the solvent was removed under reducedpressure at 100° C., the residue was treated for one hour with 20 ml ofdiethyl ether in an ultrasound bath, and the ethereal solution wasdecanted off from the brown, oily residue. The ether was removed underreduced pressure, and the solid that remained was taken up in 2 ml ofdimethylformamide, carefully covered with a layer of 10 ml of methanol,and left to crystallize at +4° C.

Yield: 0.85 g (24% of theory). Melting point: 150° C. ¹H-NMR (CD₃CN):δ=3.28 (s, 6H, OCH₃); 6.37 (m, 2H, H_(arom.)); 6.44 (d, ³J_(H-H)=3.3 Hz,2H, H_(arom.)); 6.48 (m, 2H, H_(arom.)); 6.65 (d, ³J_(H-H)=3.3 Hz, 2H,H_(arom.)); 7.44 (dt, ³J_(H-H)=8.1 Hz, ³J_(H-H)=8.1 Hz, ³J_(H-P)=1.5 Hz,2H, H_(arom.)); 7.52 (d, ³J_(H-H)=8.4 Hz, 2H, H_(arom.)); 7.64 (d,³J_(H-H)=1.8 Hz, 2H, H_(arom.)); 7.77 (d, ³J_(H-H)=1.8 Hz, 2H,H_(arom.)) ¹³C-NMR (CDCl₃): δ=60.4 (CH₃); 110.6 (C_(arom.)); 110.8(C_(arom.)); 121.4 (C_(arom.)); 121.8 (C_(arom.)); 129.2(C_(arom., ipso)); 130.2 (C_(arom.)); 130.6 (C_(arom.)); 134.4(C_(arom., ipso)); 136.7 (C_(arom., ipso)); 147.4 (C_(arom.)); 149.4(C_(arom. ipso)); 150.2 (C_(arom., ipso)); 154.3 (C_(arom., ipso))³¹P-NMR (CDCl₃) δ=−59.14

Repetition of this example using N,N-dimethylacetamide instead ofdimethylformamide gave the same product in a reaction time of 12 hours.

Example 8 Preparation of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(bis-p-fluorophenylphosphine)

100 mg of Pd₂(dibenzylideneacetone CHCl₃) were suspended together with80 mg of diphenylphosphinopropane in 10 ml of dimethylformamide underargon, and the mixture was stirred for 2 hours at room temperature,during which time a clear, orange-colored solution formed. This solutionwas transferred using a hollow needle to a Schlenk vessel in which 3.28g of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bistrifluoromethanesulfonicacid ester had been introduced. To this solution were then added afurther 10 ml of dimethylformamide, 1.50 g of triethylamine and 1.25 gof bis(p-fluorophenyl)phosphine, and then the mixture was stirred for 72hours at 100° C., a further 1.75 g of bis-(p-fluorophenyl)phosphinebeing added after 23 hours. When the reaction was complete, the solventwas removed under reduced pressure at 100° C., the residue was treatedfor one hour with 10 ml of diethyl ether in an ultrasound bath, and thesolution was decanted off from the brown, oily residue. The ether wasremoved under reduced pressure, and the residue was taken up in 2 ml ofdimethylformamide, carefully coated with a layer of 10 ml of methanol,and left to crystallize at +4° C.

Yield: 0.80 g (20% of theory). Melting point: 139° C. ¹H-NMR (CD₃CN):δ=3.35 (s, 6H, OCH₃); 6.88-7.13 (m, 14H, H_(arom.)); 7.16-7.27 (m, 4H,H_(arom.)); 7.46 (d, ³J_(H-H)=8.1 Hz, 2H, H_(arom.)) ¹³C-NMR (CDCl₃):δ=60.2 (CH₃); 115.5 (C_(arom.)); 115.8 (C_(arom.)); 128.7(C_(arom., ipso)); 130.2 (C_(arom.)); 130.7 (C_(arom.)); 131.7(C_(arom., ipso)); 132.7 (C_(arom., ipso)); 134.6 (C_(arom.)); 136.2(C_(arom.)); 137.8 (C_(arom., ipso)); 154.3 (C_(arom., ipso)); 161.4(C_(arom., ipso)); 161.9 (C_(arom. ipso)); 164.7 (C_(arom., ipso));165.2 (C_(arom., ipso)) ³¹P-NMR (CDCl₃) δ=−16.01 ¹⁹F-NMR (CDCl₃) δ=113.6(s, Ar—F); −112.3 (s, Ar—F)

Example 9 Preparation of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(bis-3,5-dimethylphenylphosphine)

100 mg of Pd₂(dibenzylideneacetone)₃ CHCl₃ were suspended together with80 mg of diphenylphosphinopropane in 10 ml of dimethylformamide underargon, and the mixture was stirred for 1 hour at room temperature,during which time a clear orange-colored solution was formed. Thissolution was transferred using a hollow needle to a Schlenk vessel intowhich 2.70 g of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bistrifluoromethanesulfonicacid ester had been introduced. To this solution were added a further 10ml of dimethylformamide, 1.60 g of N,N-diisopropylethylamine, and 2.43 gof bis-(3,5-dimethylphenyl)-phosphine, and then the mixture was stirredfor a total of 115 hours at 100° C., a further 0.25 g ofbis-(3,5-dimethylphenyl)phosphine being added after 75 hours, and afurther 0.32 g of bis-(3,5-dimethylphenyl)phosphine being added after100 hours. When the reaction was complete, the dimethylformamide wasremoved under reduced pressure at 100° C., and the residue was subjectedto flash column chromatography over silica gel 60 using toluene aseluent. The solvent was removed under reduced pressure, and the residuewas taken up in 2 ml of dimethylformamide, carefully coated with a layerof 8 ml of methanol, and left to crystallize at +4° C. Following removalof the 1 st precipitation fraction, the filtrate was concentrated to 1ml at 100° C. and, again after coating with methanol, left tocrystallize.

Yield: 1.50 g (42% of theory). Melting point: 225° C. ¹H-NMR (CD₃CN):δ=2.14 (s, 12H, Ar—CH₃); 2.22 (s, 12H, Ar—CH₃); 3.27 (s, 6H, OCH₃);6.80-6.90 (m, 12H, H_(arom.)); 6.99 (d, ³J_(H-H)=9.0 Hz, 2H, H_(arom.));7.31 (d, ³J_(H-H)=9.0 Hz, 2H, H_(arom.)) ³¹P-NMR (CDCl₃): δ=−13.73

Example 10-1 Preparation of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(bis-2-(N-methylpyrrolyl)phosphine)

a) Preparation of di(N-methylpyrrolyl)ethyl Phosphinite

To a solution of 38.61 g of methylpyrrole in 200 ml of diethyl etherwere added dropwise, at 0° C., first 297.5 ml of a 1.6 molar solution ofn-butyllithium in hexane and then 35.0 g of dichloroethyl phosphinite.The reaction solution was then stirred overnight at room temperature,and then the solvent was stripped off under reduced pressure. Theresidue that remained was taken up in 200 ml of petroleum ether, theinsoluble lithium salts were filtered off, and the solvent was strippedoff from the filtrate. The residue that was formed during this operationwas fractionally distilled.

Yield: 14.14 g (25% of theory). Boiling point: 125-130° C. at 0.17 torr.³¹P-NMR shift: 76.54 ppm in CDCl₃

b) Preparation of di-2-(N-methylpyrrolyl)-phosphine

To a suspension of 0.75 g of lithium aluminum hydride in 20 ml oftetrahydrofuran were added dropwise, at −70° C., 2.15 g oftrimethylchlorosilane, and the suspension was then stirred for 2 hoursat room temperature. A solution of 2.15 g of di(N-methylpyrrolyl)ethylphosphinite in 10 ml of tetrahydrofuran was then added dropwise. Thereaction mixture was stirred for 20 hours at room temperature. Thereaction mixture was then hydrolyzed with 1 g of water (until there wasno further evolution of hydrogen), the solvent was stripped off underreduced pressure, and the residue that remained was taken up inpetroleum ether. After the insoluble aluminum and lithium salts had beenfiltered off, the solvent was stripped off from the filtrate and theresidue that formed during this operation was dried under reducedpressure.

Yield: 30% of theory. ³¹P-NMR shift: −111.36 ppm in C₆D₆

c) Synthesis of the Compound Stated at the Outset

The procedure was as described in Example 6, but usingdi-2-(N-methylpyrrolyl)phosphine instead of diphenylphosphine.

¹H-NMR (CDCl₃): δ=3.04 (s, 6H); 3.26 (s, 6H); 3.66 (s, 6H); 5.98-6.01 (m2H); 6.65 (t, 2H); 6.07-6.1 (m, 2H); 6.17 (t, 2H); 6.65 (t, 2H);6.84-6.87 (m, 2H); 6.88-6.93 (m, 2H); 7.3 (d, 2H) ³¹P-NMR (CDCl₃):δ=−58.75

Example 10-2 Preparation of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(bis-3,5-dimethoxyphenyl)phosphine)

In a heat-dried Schlenk vessel with a Teflon stirrer bar, 26.4 mg of[Pd₂(dba)₃].CHCl₃ and 1.1 mg of diphenylphosphinopropane were suspendedin 3 ml of dimethylacetamide, and the mixture was stirred for 30 min atroom temperature, during which operation the solution became clear andassumed a red color. This solution was transferred using a hollow needleinto a Schlenk vessel in which 0.95 g of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bistrifluoromethanesulfonicacid ester and 1.1 g of bis(3,5-dimethoxyphenyl)phosphine in 10 ml ofdimethylacetamide had been introduced. 0.64 g of diisopropylethylaminewere then added and the mixture was heated to 80° C. After 72 hours, thesolvent was removed under reduced pressure, and the residue was taken upin 2 ml of toluene and purified using flash-chromatography over silicagel with toluene as eluent. The yellowish oil that formed was taken upin diethyl ether, and the ether was then removed under reduced pressure.This gave 0.78 g of the product as a pale yellow voluminous substance.

Yield: 53% of theory ³¹P-NMR-(CDCl₃): δ=−10.61 MS (SIMS): m/z (%)=890.9(9, M⁺), 753.0 (5, M⁺C₈H₁₀O₂), 584.9 [100, M⁺—P(C₈H₁₀O₂)₂], 448.9 [2,M⁺—P(C₈H₁₀O₂)₂—C₈H₁₀O₂],384.9 3, 337.05, 280.9 {19, M⁺—[P(C₈H₁₀O₂)₂]₂}220.9 (28), 206.9 (33), 146.9 (70).

Example 11 Preparation of the Catalyst(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(di-3,5-dimethylphenylphosphino)-bis(3,3,3-trifluoraceto)-ruthenium

0.0431 g of (cyclooctadiene)Ru(η³-methallyl)₂ and 0.1033 g of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(bis-3,5-dimethylphenylphosphine)were dissolved in 5 ml of methylene chloride, 5 ml of methanol wereadded, and then, with stirring, 21.5 μl of trifluoroacetic acid wereadded. After the mixture had been stirred for 24 hours at roomtemperature, the solvent was removed under reduced pressure and theorange-colored residue was dried for 2 hours under reduced pressure.

Example 12 Preparation of the Catalyst(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(bis-4-fluorophenylphosphino)-3,3,3-trifluoroaceto)ruthenium

The preparation was as described in Example 11, but now using thecorresponding bis-4-fluorophenylphosphine instead of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(bis-3,5-dimethylphenylphosphine).

Example 13-1 Preparation of the Catalyst(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis-(di-2-furylphosphino)-bis(3,3,3-trifluoroaceto)ruthenium

The preparation was as described in Example 11, but now using thecorresponding bis-2-furylphosphine instead of(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(bis-3,5-dimethylphenylphosphine).

Example 13-2 Preparation of the Catalyst(5,5′-dichloro-6,6′-dimethoxybiphenyl-2,2′-diyl)-bis(3,5-dimethoxyphenylphosphino)-bis(3,3,3-trifluoroaceto)ruthenium

432 mg of the product from Example 10-2 were added to a solution of 155mg of (cyclooctadiene)Ru(η³-methallyl)₂ in CH₂Cl₂, and the mixture wasstirred for 1 hour at room temperature. The solvent was then removedunder reduced pressure. The product was formed as a dark green solid inquantitative yield.

³¹P-NMR-(d⁴-MeOH): δ=64.22 MS (SIMS): m/z (%)=1143.2, 991.2 [12,M⁺—(CO₂CF₃)₂], 585.3 [M⁺—Ru(CO₂CF₃)₂—P(C₈H₁₀O₂)₂], 147.1 (19), 132.9(28), 73.1 (100).

Examples 14 to 20 Hydrogenations with Catalysts from Examples 11 to 13.

20 μmol of catalyst were dissolved in 5 ml of methanol, 2.0 ml ofdimethyl itaconate, and 0.100 g of diglyme (GC standard) were added, andthe mixture was reacted with hydrogen in a glass autoclave (1 bar of H₂)or steel autoclave (70 bar of H₂). When the reaction period had expired,and optionally following decompression, a vacuum was applied to removedissolved hydrogen, and the catalyst/product solution was then analyzedby gas chromatography. The results are summarized in Table 1.

TABLE 1 Catalyst Reaction from Temp. Pressure time Conversion YieldExample Example (° C.) (bar) (h) (%) (%) TOF/h⁻¹ ee (%) Configuration 1413-1 23 70 15 99.9 100 6.6 65.5 (S) 15 13-1 50 1 1 17.0 12.2 12.3 92.5(S) 16 12 22 1 1 70 71 70 94.7 (S) 17 12 22 1 0.7 35 34 49.8 96.2 (S) 1812 50 1 0.5 100 100 198 95.5 (S) 19 11 22 1 1 100 100 22 94.7 (S) 20 1150 1 0.5 100 100 >200 96.9 (S)

Examples 21 to 24 Hydrogenations with in Situ Catalyst Systems

20 μmol of (norbornadiene)₂RhPF₆ were dissolved with in each case 20mmol of the ligands from Examples 7 to 9 in 5 ml of a solvent. Whenusing the ligand from Example 7, the solvent was methanol, and whenusing the ligands from Examples 8 and 9, the solvent was a 1:1 mixtureof methylene chloride and methanol. The mixture obtained was stirred for1 hour at 40° C., then the solvent was removed under reduced pressure,and then 5 ml of methanol were added. 2.0 mmol of dimethyl itaconate and0.100 g of diglyme (GC standard) were added, and the mixture was reactedwith hydrogen in a glass autoclave (1 bar of H₂) or steel autoclave (70bar of H₂). After the reaction time had expired, and optionally afterdecompression, a vacuum was applied to remove dissolved hydrogen, andthe catalyst/product solution was then analysed using gaschromatography. The results are summarized in Table 2.

TABLE 2 Reaction Temp. Pressure time Conversion Yield Example Ligand (°C.) (bar) (h) (%) (%) TOF/h⁻¹ ee (%) Configuration 21 from 24 1 1 95 100120 31.4 (S) Example 7 22 from 22 70 0.5 97 95 193 14.3 (S) Example 7 23from 22 1 1 12 16 22 26 (S) Example 8 24a) from 22 1 1 100 100 98.5 78.3(S) Example 9 24b) from 22 100 0.5 100 100 196 58.5 (S) Example 9 24c)from 50 100 0.5 100 100 >200 74.2 (S) Example 9

Examples 25 to 28 Hydrogenations with the Catalyst from Example 13-2

In a heat-dried glass autoclave (a steel autoclave was used in Example27) charged with argon, a solution of 0.32 g of dimethyl itaconate,0.024 g of the catalyst from Example 13-2, 0.1 g of diglyme, and 5 ml ofmethanol was added and then 1 bar (in Example 27 70 bar) of hydrogen wasfed in. Then, at the temperature given in Table 3, the mixture wasvigorously stirred for 30 min. Then, to remove the hydrogen, a samplewas taken to determine the conversion (GC), the mixture that remainedwas subjected to flash distillation, and the enantiomer excess in thedistillate was determined.

In Example 28, 0.64 g of dimethyl itaconate were used. Details are givenin Table 3.

TABLE 3 Temp. Pressure Conversion Example (° C.) (bar) (%) TOF/h⁻¹ ee(%) 25 22 1 99.9 138 92.4 26 40 1 99.7 >200 92.4 27 22 70 99.7 >200 55.628 22 1 38.3 136 91.2

1. Racemic and enantiomerically pure biphenyldiols of the formula (V)

and the corresponding racemic and enantiomerically pure triflatecompounds thereof, where R¹ and R² are H, R³ is chlorine, and R⁴ ismethoxy.
 2. Compounds of the formula (V)

wherein R¹ and R² are hydrogen and R³ and R⁴ are C₁-C₄-alkoxy, fluorine,or chlorine.